Cation Homeostasis: Coordinate Regulation of Polyamine and Magnesium Levels in Salmonella

Polyamines are organic cations that are important in all domains of life. Here, we show that in Salmonella, polyamine levels and Mg²⁺ levels are coordinately regulated and that this regulation is critical for viability under both low and high concentrations of polyamines. Upon Mg²⁺ starvation, polyamine synthesis is induced, as is the production of the high-affinity Mg²⁺ transporters MgtA and MgtB. Either polyamine synthesis or Mg²⁺ transport is required to maintain viability. Mutants lacking the polyamine exporter PaeA, the expression of which is induced by PhoPQ in response to low Mg²⁺, lose viability in the stationary phase. This lethality is suppressed by blocking either polyamine synthesis or Mg²⁺ transport, suggesting that once Mg²⁺ levels are reestablished, the excess polyamines must be excreted. Thus, it is the relative levels of both Mg²⁺ and polyamines that are regulated to maintain viability. Indeed, sensitivity to high concentrations of polyamines is proportional to the Mg²⁺ levels in the medium. These results are recapitulated during infection. Polyamine synthesis mutants are attenuated in a mouse model of systemic infection, as are strains lacking the MgtB Mg²⁺ transporter. The loss of MgtB in the synthesis mutant background confers a synthetic phenotype, confirming that Mg²⁺ and polyamines are required for the same process(es). Mutants lacking PaeA are also attenuated, but deleting paeA has no phenotype in a polyamine synthesis mutant background. These data support the idea that the cell coordinately controls both the polyamine and Mg²⁺ concentrations to maintain overall cation homeostasis, which is critical for survival in the macrophage phagosome. IMPORTANCE Polyamines are organic cations that are important in all life forms and are essential in plants and animals. However, their physiological functions and regulation remain poorly understood. We show that polyamines are critical for the adaptation of Salmonella to low Mg²⁺ conditions, including those found in the macrophage phagosome. Polyamines are synthesized upon low Mg²⁺ stress and partially replace Mg²⁺ until cytoplasmic Mg²⁺ levels are restored. Indeed, it is the sum of Mg²⁺ and polyamines in the cell that is critical for viability. While Mg²⁺ and polyamines compensate for one another, too little of both or too much of both is lethal. After cytoplasmic Mg²⁺ levels are reestablished, polyamines must be exported to avoid the toxic effects of excess divalent cations.